The present invention relates to .alpha.,.omega.-diamino acid derivatives which are dual inhibitors of neutral endopeptidase and angiotensin converting enzyme, useful in the treatment of cardiovascular disorders.
Cardiovascular disorders which may be treated with compounds of the present invention include hypertension, congestive heart failure and renal insufficiency.
The renin-angiotensin system is a complex hormonal system comprised of a large molecular weight precursor, angiotensinogen, two processing enzymes, renin and angiotensin converting enzyme (ACE), and a vasoactive mediator, angiotensin II (A II). The enzyme renin catalyzes the cleavage of angiotensinogen into the decapeptide angiotensin I (A I), which has minimal biological activity on its own and is converted into the active octapeptide A II by ACE. A II has multiple biological actions on the cardiovascular system, including vasoconstriction, activation of the sympathetic nervous system, stimulation of aldosterone production, antinatriuresis, stimulation of vascular growth and stimulation of cardiac growth. A II functions as a pressor hormone and is involved in the pathophysiology of several forms of hypertension.
Angiotensin converting enzyme (ACE) is a zinc-metalloprotease which converts A I to A II. Inhibitors of this enzyme, which have been widely studied, include the drugs captopril, enalapril, lisinopril and spirapril. Although a major mode of action of ACE inhibitors involves prevention of formation of the vasoconstrictor peptide A II, it has been reported in Hypertension, 16, 4 (1990) p. 363-370 that ACE cleaves a variety of peptide substrates, including the vasoactive peptides bradykinin and substance P. Prevention of the degradation of bradykinin by ACE inhibitors has been demonstrated, and the activity of the ACE inhibitors in some conditions has been reported in Circ. Res., 66, 1 (1990) p. 242-248 to be mediated by elevation of bradykinin levels rather than inhibition of A II formation.
Neutral endopeptidase (EC 3.4.24 11; enkephalinase; atriopeptidase; NEP) is a zinc-containing metalloprotease which cleaves a variety of peptide substrates on the amino terminal side of aromatic amino acids. Substrates for this enzyme include, but are not limited to, atrial natriuretic factors (ANF), brain natriuretic peptide, met and leu enkephalin, bradykinin, neurokinin A, and substance P.
Inhibitors of NEP lower blood pressure and exert ANF-like effects such as diuresis and increased cyclic guanosine 3',5'-monophosphate (cGMP) excretion in some forms of experimental hypertension. The antihypertensive action of NEP inhibitors is mediated through ANF because antibodies to ANF will neutralize the reduction in blood pressure.
U.S. Pat. No. 4,749,688 also established the antihypertensive action of NEP inhibitors and that co-administration of an ACE inhibitor and a NEP inhibitor results in a greater reduction of blood pressure than observed with either agent alone. The antihypertensive effect is best manifested under conditions in which the renin angiotensin system is suppressed, as reported by Sybertz et al in J. Parmacol. Exp. Ther., 250, 2 (1989) pp. 624-631 and in Hypertension, 15, 2 (1990) pp. 152-161. For example, NEP inhibitors reduce blood pressure effectively in the Desoxy-corticosterone salt (DOCA) hypertensive rat, a volume-dependent, renin-suppressed model of hypertension, but are less effective under conditions in which the renin-angiotensin system is activated, such as in the spontaneously hypertensive rat (SHR) and in the two kidney Goldblatt hypertension model. Studies in the SHR and in the two-kidney Goldblatt hypertension model using a prodrug of the NEP inhibitor N-[2(S)-mercaptomethyl-3-(2-methylphenyl)propionyl]-methionine in combination with the ACE inhibitor spirapril demonstrated the greater efficacy of the combination compared to either drug alone. However, this interaction was inhibited in SHR which had been nephrectomized, a manipulation which markedly suppresses renin levels.
An explanation of this interactive effect of ACE inhibitors and NEP inhibitors on blood pressure is that suppression of the renin angiotensin system allows for full expression of the ANF-like antihypertensive effect of the NEP inhibitor. A II and ANF exert opposite effects on the cardiovascular system and it has been proposed by Johnston et al in Am. J. Med., 87, (Suppl 6) (1990) p. 24S-28S that these two hormonal systems act to counterbalance one another.
Compounds possessing dual activity as NEP-ACE inhibitors have been reported. European Patent Publication EP 0358398 discloses cycloalkyl-substituted glutaramides of the formula ##STR2## wherein: A completes a 5 or 6 membered carbocyclic ring; R.sup.1 is H or alkyl; R and R.sup.4 are H, alkyl, cycloalkyl, benzyl or an alternative biolabile ester-forming group; Y is a bond or an alkylene group; R.sup.2 is H, aryl, heterocyclyl, or a carboxamido, carbamoyl, sulfamoyl or sulfonamido group; and R.sup.3 is a group of the formula ##STR3## wherein the benzene ring of said group is optionally substituted;
European Patent Publication EP 0474553 discloses actinoin derivatives of the formula ##STR4## wherein R.sup.1 is sulfoxymethyl, carboxyl, carboxamido, hydroxyaminocarbonyl or alkoxycarbonyl; and R.sup.2 is hydroxy, alkoxy, hydroxyamino or sulfoxyamino;
European Patent Publication EP 0481522 discloses compounds of the formula ##STR5## wherein: A.sub.1 and A.sub.2 are independently H or --COOR.sub.4 ; provided that where A.sub.1 is H, A.sub.2 is --COOR.sub.4, and where A.sub.1 is --COOR.sub.4, A.sub.2 is H;
B.sub.1 and B.sub.2 are independently H, OH, C.sub.1 -C.sub.4 alkoxy, aryl or aryl(C.sub.1 -C.sub.4 alkyl); or, where B.sub.1 and B.sub.2 are attached to adjacent carbon atoms, B.sub.1 and B.sub.2 together with the carbons to which they are attached comprise a benzene or methylenedioxy ring; PA0 R.sub.2 is H, C.sub.1 -C.sub.8 alkyl, --CH.sub.2 --O--(CH.sub.2).sub.2 --O--CH.sub.3, aryl or aryl(C.sub.1 -C.sub.4 alkyl); PA0 R.sub.3 is H, acetyl, --CH.sub.2 --O--C(O)--CCH.sub.3, or benzoyl; PA0 R.sub.4 is H, --CH.sub.2 --O--C(O)--CCH.sub.3, C.sub.1 -C.sub.4 alkyl, diphenylmethyl, aryl or aryl(C.sub.1 -C.sub.4 alkyl); and PA0 n is 0 or 1; PA0 R.sup.1 is hydrogen or a group of the formula R.sup.7 R.sup.8 N--; PA0 R.sup.2 is hydrogen, lower alkyl, cyclolower alkyl, aryllower alkyl or heteroaryllower alkyl; and R.sup.3 is hydrogen, lower alkyl or cyclolower alkyl; or R.sup.2 and R.sup.3, together with the carbon to which they are attached, comprise a 3-7 membered carbocyclic ring; PA0 R.sup.4 is hydrogen, lower alkyl, aryl lower alkyl or heteroaryllower alkyl; PA0 R.sup.5 and R.sup.6 are independently selected from the group consisting of hydroxy, lower alkoxy, amino, aryllower alkoxy, lower alkylamino and di(lower alkyl)amino; PA0 R.sup.7 is R.sup.9 C(O)-- or R.sup.10 SO.sub.2 --; and R.sup.8 is hydrogen, lower alkyl, aryllower alkyl or aryl; or R.sup.7 and R.sup.8, together with the nitrogen to which they are attached, comprise a 5-7 membered ring; PA0 R.sup.9 is lower alkyl, aryllower alkyl, aryl, heteroaryllower alkyl, heteroaryl, lower alkoxy, aryllower alkoxy, amino, lower alkylamino or di-(lower alkyl)amino; PA0 R.sup.10 is lower alkyl, aryl lower alkyl, aryl, heteroaryl lower alkyl, amino, lower alkylamino, di-(lower alkyl)amino or heteroaryl; PA0 n is 1, 2, 3, 4 or 5; PA0 m is 1, 2, 3, 4 or 5;
having activity as inhibitors of both neutral endopeptidase and angiotensin converting enzyme; and Gros, et al., Proc. Natl. Acad. Sci. USA, 88, (1991) pp 4210-4214, discloses dual inhibitors of ACE and NEP of the formula ##STR6## wherein R is H or CH.sub.3 C(O)--, R.sup.1 is H or benzyl, and R.sup.2 is H or methyl.